PROJECT SUMMARY/ABSTRACT The mission of our Perimenopause in Brain Aging and Alzheimer?s Disease Program Project is to discover biological transformations in brain that occur during the perimenopausal transition that lead to endophenotypes predictive of risk for Alzheimer?s disease (AD). Our goals are to identify the mechanisms by which these transformations occur and to translate these discoveries into strategies to prevent conversion to an at-Alzheimer's-risk phenotype. The mission for this competitive Supplement to P01AG026572 Perimenopause in Brain Aging and Alzheimer's Disease is to investigate whether the perimenopause to menopause transition, a neuroendocrine transition state specific to the female, drives progression of Alzheimer?s disease (AD) endophenotype in women, thereby playing a determinant role in the well-established increased prevalence of AD in women. As late-onset AD accounts for the greatest incidence and prevalence of the disease, determining sex-specific molecular mechanisms relevant to AD onset and progression has the potential for greatest impact. Further, examination of early stage transitions of risk has the greatest potential for identification of therapeutic targets to change the trajectory of the disease to prevent, delay and potentially reverse course of developing AD. To achieve this goal, we propose to perform longitudinal multi-modality brain imaging examinations in a cohort of prospectively recruited cognitively normal women at risk for AD, who will undergo Magnetic Resonance (MR) and Positron Emission Tomography (PET) scans measuring volumetrics, structural connectivity, mitochondrial bioenergetics, glucose metabolism, and fibrillary amyloid-beta deposition at baseline and 2 years later. Our plan is to leverage our active P01AG026572 (PI R. Brinton; Site-PI L. Mosconi) to perform longitudinal exams on the 78 female patients who are scheduled to complete baseline evaluations as part of the grant. Outcomes of our analyses will elucidate molecular mechanisms that emerge in midlife and that increase risk of developing AD later in life. Collectively, these data will provide therapeutic targets for sex-based precision medicine interventions during the prodromal phase of late-onset AD, when the potential to reverse, prevent and delay AD progression is greatest. Research proposed herein address goals of the National Alzheimer's Project Act (NAPA) to prevent and effectively treat AD by 2025 and the NIA Alzheimer's Disease Research Summit 2015 key objectives of sex and metabolic determinants of AD.